Synthesis of Marine Polyacetylenes Callyberynes A-C by Transition-Metal-Catalyzed Cross-Coupling Reactions to sp Centers Susana Lo´pez,* Francisco Ferna´ndez-Trillo, Pilar Mido´n, Luis Castedo, and Carlos Saa´ Departamento de Quı´mica Orga´ nica, Facultade de Quı´mica, UniVersidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
[email protected] ReceiVed December 20, 2005
Efficient total syntheses of the sponge-derived hydrocarbon polyacetylenes callyberynes A-C have been achieved using metal-catalyzed cross-coupling reactions of highly unsaturated 1,3-diyne fragments as the key steps, namely: Cadiot-Chodkiewicz reaction under Alami’s optimized conditions (sp-sp), sequential Sonogashira reaction of a cis,cis-divinyl dihalide (sp2-sp), and Kumada-Corriu reaction of an unactivated alkyl iodide (sp3-sp). This last approach constitutes the first application of a metalcatalyzed sp3-sp Kumada-Corriu cross-coupling reaction to the synthesis of a natural product.
Introduction The carbon-carbon triple bond is a ubiquitous structural feature of organic molecules.1 Conjugated polyacetylenes are common structural units in a large number of natural products, many of which exhibit potent and varied biological activities and play important ecological roles.2 In addition, they are also key structural moieties in synthetic compounds with unusual electrical, optical, or structural properties, which have found applications in materials science.3 Consequently, renewed interest has recently appeared in the synthetic studies of both natural and unnatural acetylenic compounds.4 (1) Stang, P. J., Diederich, F., Eds. Modern Acetylene Chemistry; WileyVCH: Weinheim, 1995. (2) (a) Bohlmann, F.; Burkhart, F, T,; Zero, C. Naturally Occurring Acetylenes; Academic Press: New York, 1973. (b) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2005, 22, 15-61 and previous reports in this series.
Transition-metal-catalyzed cross-coupling reactions are widely recognized as selective, high-yielding methods for the synthesis of organic compounds and have proven to be one of the most powerful arsenals for the formation of carbon-carbon bonds to sp centers.5 However, the highly reactive nature of the intermediates involved in the total synthesis of conjugated polyacetylenes often presents a major challenge. The vast majority of the metal-catalyzed acetylenic crosscoupling processes requires substrates having an sp or sp2 carbon (3) (a) Luu, T.; Elliott, E.; Slepkov, A. D.; Eisler, S.; McDonald, R.; Hegmann, F. A.; Tykwinski, R. R. Org. Lett. 2005, 7, 51-54. (b) Eisler, S.; Slepkov, A. D.; Elliot, E.; Luu, T.; McDonald, R.; Hegmann, F. A.; Tykwinski, R. R. J. Am. Chem. Soc. 2005, 127, 2666-2676. (c) Umeda, R.; Morinaka, T.; Sonoda, M.; Tobe, Y. J. Org. Chem. 2005, 70, 61336136. (d) Marsden, J. A.; Haley, M. M. J. Org. Chem. 2005, 70, 1021310226. (4) For a recent review on the synthesis of naturally occurring polyyynes, see: Shi Shun, A. L. K.; Tykwinski, R. R. Angew. Chem., Int. Ed. 2006, 45, 1034-1057. 10.1021/jo052609u CCC: $33.50 © 2006 American Chemical Society
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Synthesis of Marine Polyacetylenes Callyberynes A-C
at or immediately adjacent to an electrophilic center. Polyacetylenic compounds are usually obtained through coupling of two acetylenic fragments.6 Symmetrical 1,3-diynes can be prepared by oxidative coupling of terminal alkynes. Unsymmetrically disubstituted 1,3-diynes are more often obtained by the Cadiot-Chodkiewicz cross-coupling of a bromoacetylene with a terminal alkyne in the presence of a copper(I) salt and an aliphatic amine.7 Some catalytical versions have been described together with examples of Pd-Cu cocatalysis.8 Alami9 has reported improved conditions for the coupling of terminal alkynes with 1-iodoalkynes in pyrrolidine that employ a copper catalyst and do not require a palladium cocatalyst. This optimized version can be advantageously used in the case of aliphatic 1-alkynes, which are known to give low yields of crosscoupling products under classical Cadiot-Chodkiewicz conditions. The transition-metal-catalyzed cross-coupling reaction of metal acetylides with vinyl/aryl halides is an important reaction in organic synthesis since it provides a straight method for sp2sp carbon-carbon coupling.10 The palladium-catalyzed crosscoupling reactions of terminal alkynes with sp2 halides/triflates, in the presence (Sonogashira-Hagihara alkynylation)11 or in the absence (Heck alkynylation)12 of a copper cocatalyst, are even more useful synthetically and have been extensively used in the stereospecific synthesis of conjugated enynes.13 Palladium-catalyzed couplings in which the electrophile is sp3-hybridized have been, however, rather uncommon.14 Slow oxidative addition of the alkyl halide/triflate to palladium and facile intramolecular β-hydride elimination of the alkylmetal intermediate are two likely causes for this comparative lack of attention. However, a number of conditions have been developed (5) (a) Miyaura, N. Cross-Coupling Reactions. In Topics in Current Chemistry; Springer-Verlag: Berlin, 2000; Vol. 219. (b) Schlosser, M. Organometallics in Synthesis, 2nd ed.; John Wiley & Sons: Chichester, 2002. (c) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004. (d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442-4489. (6) (a) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 551-562. (b) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2633-2657. (7) Cadiot, P. C. R.; Chodkiewicz, W. Coupling of Acetylenes in Chemistry of Acetylenes; Viehe, H. G., Ed.; Marcel Dekker: New York, 1969. (8) (a) Wityak, J.; Chan, J. B. Synth. Commun. 1991, 21, 977-979. (b) Cai, C.; Vasella, A. HelV. Chim. Acta 1995, 78, 2053-2064. (9) Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763-2766. (10) (a) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 521-549. (b) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp 203-229. (c) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566-1568. (d) Negishi, E.-i.; Anastasia, L. Chem. ReV. 2003, 103, 1979-2017. (11) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467-4470. (b) Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proced. Int. 1995, 27, 127-160. (c) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46-49. (d) Sonogashira, K. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley: New York, 2002; pp 493529. (12) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93, 259263. (13) For some recent applications in the synthesis of natural products, see: (a) Guilford, W. J.; Bauman, J. G.; Skuballa, W.; Bauer, S.; Wei, G. P.; Davey, D.; Schaefer, C.; Mallari, C.; Terkelsen, J.; Tseng, J.-L.; Shen, J.; Subramanyam, B.; Schottelius, A. J.; Parkinson, J. F. J. Med. Chem. 2004, 47, 2157-2165. (b) Murakami, Y.; Nakano, M.; Shimofusa, T.; Furuichi, N.; Katsumura, S. Org. Biomol. Chem. 2005, 3, 1372-1374. Some recent applications in the chemistry of materials, see: (c) Miljanic, O. S.; Holmes, D.; Vollhardt, K. P. C. Org. Lett. 2005, 7, 4001-4004. (d) Golovkova, T. A.; Kozlov, D. V.; Neckers, D. C. J. Org. Chem. 2005, 70, 5545-5549.
recently to enhance the reactivity of the aliphatic C-X bonds and/or to stabilize the resulting organometallic intermediate so that the desired coupling can be achieved.15 Regarding alkynylation, to the best of our knowledge, only two examples are described in the literature employing terminal alkynes and electrophilic sp3 centers.16 Luh17 has reported that Pd2(dba)3Ph3P-catalyzed Kumada-Corriu coupling reactions of unactivated alkyl bromides or iodides with an alkynyl nucleophile (Mg or Li) led to Csp3-Csp bond formation in good yields; the source of palladium appears to be decisive (palladium acetate is not an effective catalyst), and Ph3P performs as the best ligand in what seems to be a reductive elimination-controlled process. On the other hand, Fu18 has developed a Pd/N-heterocyclic carbene-based catalyst that achieves Sonogashira coupling of terminal alkynes with an array of fuctionalized, unactivated, β-hydrogen-containing alkyl bromides and iodides, under mild conditions. As part of our ongoing projects on developing efficient and selective routes to natural and synthetic polyenes and polyenynes,19 we became interested in a synthetically unexplored, rapidly growing group of linear, bioactive marine polyacetylenes isolated from the family Callyspongiidae. Fusetani20 and Umeyama21 have independently reported the isolation, from Japanese Callyspongia sp., of three C21 hydrocarbon polyacetylenes: callyberyne A (also referred to as callypentayne) (1), callyberyne B (2), and callyberyne C (also referred to as callytetrayne) (3) (Scheme 1). The three metabolites were structurally related to the known (-)-siphonodiol (4),22 and biogenetically, they were considered most likely to be produced by decarboxylation of a C22 fatty acid precursor in the sponge. As some other members of this family,23 callyberynes A (1) and C (3) exhibited potent metamorphosis-inducing activity in the ascidian Halocynthia roretzi, with ED100 values of 0.25 µg/ mL.20 (14) (a) Billington, D. C. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 413-434. (b) Tamao, K. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 435-480. (c) Ca´rdenas, D. J. Angew. Chem., Int. Ed. 1999, 38, 3018-3020. (d) Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem. ReV. 2000, 100, 3187-3204. (e) Ca´rdenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384-387. (15) (a) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004, 346, 15251532. (b) Fu, G. C. J. Org. Chem. 2004, 69, 3245-3249. (c) Netherton, M. R.; Fu, G. C. In Topics in Organometallic Chemistry; Springer GmbH: Heidelberg, 2005; Vol. 14, pp 85-108. (d) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674-688. (16) Examples of metal-catalyzed cross-coupling reactions of alkynyl stannanes with alkyl halides have been already described; see, for instance, ref 14d. (17) Yang, L.-M.; Huang, L.-F-; Luh, T.-Y. Org. Lett. 2004, 6, 14611463. (18) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 1364213643. (19) For some recent publications of our group in the chemistry and biology of polyenes and polyenynes, see: (a) Martı´nez-Espero´n, M. F.; Rodrı´guez, D.; Castedo, L.; Saa´, C. Org. Lett. 2005, 7, 2213-2216. (b) Lo´pez, S.; Rodrı´guez, V.; Montenegro, J.; Saa´, C.; Alvarez, R.; Lo´pez, C. S.; de Lera, A. R.; Simo´n, R.; Lazarova, T.; Padro´s, E. ChemBioChem 2005, 6, 2078-2087. (20) Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N. J. Nat. Prod. 1997, 60, 126-130. (21) Umeyama, A.; Nagano, C.; Arihara, S. J. Nat. Prod. 1997, 60, 131133. (22) (a) Tada, H.; Yasuda, F. Chem. Lett. 1984, 779-780. (b) Fusetani, N.; Sugano, M.; Matsunaga, S.; Hashimoto, K. Tetrahedron Lett. 1987, 28, 4311-4312. (23) The family includes around 20 structurally related compounds, among them four C21 hydrocarbons, four C22 alcohols, five triols, two sulfates, one dihydro derivative, and one tetrahydro derivative. See refs 2b, 25, 26, and references cited therein.
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Lo´pez et al. SCHEME 1.
Retrosynthetic Analysis
The highly unsaturated nature of these new marine polyacetylenes prompted us to investigate their synthesis by routes that would allow us to apply new cross-coupling reactions and/ or to test standard cross-coupling reactions by employing structurally complex building blocks.24 As a result, we have already reported a communication on the synthesis of hydrocarbon callyberynes A (1) and B (2),25 and we have recently described the first, stereoselective total synthesis of the parent compound (-)-siphonodiol (4)26 using highly convergent approaches that involved optimized Cadiot-Chodkiewicz and sequential Sonogashira cross-coupling reactions as the key steps. We want to disclose herein the full account of our efforts toward the total synthesis of callyberynes A-B together with the first total synthesis of the related callyberyne C (3). The overall retrosynthetic analysis is summarized in Scheme 1. The convergent approaches to the three polyacetylenes rely on bond disconnections at the central sp centers and employ transition-metal-catalyzed alkynylation reactions (sp-sp, sp2sp, or sp3-sp) as the pivotal steps. The high structural resemblance of the three natural products will allow the use of common synthetic building blocks. The strategy requires the preparation of several highly unsaturated, monoprotected in(24) For some recent syntheses of natural polyacetylenes, see: (a) Carpita, A.; Braconi, S.; Rossi, R. Tetrahedron: Asymmetry 2005, 16, 2501-2508. (b) Gung, B. W.; Gibeau, C.; Jones, A. Tetrahedron: Asymmetry 2005, 16, 3107-3114. (c) Kirkham, J. E. D.; Courtney, T. D. L.; Lee, V.; Baldwin, J. E. Tetrahedron 2005, 61, 7219-7232. (d) Pereira, A. R.; Cabezas, J. A. J. Org. Chem. 2005, 70, 2594-2597. (e) Yun, H.; Chou, T.-C.; Dong, H.; Tian, Y.; Li, Y.-m.; Danishefsky, S. J. J. Org. Chem. 2005, 70, 1037510380. For a recent review, see ref 4. (25) Lo´pez, S.; Ferna´ndez-Trillo, F.; Castedo, L.; Saa´, C. Org. Lett. 2003, 5, 3725-3728. (26) Lo´pez, S.; Ferna´ndez-Trillo, F.; Mido´n, P.; Castedo, L.; Saa´, C. J. Org. Chem. 2005, 70, 6346-6352.
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termediates so the choice of suitable acetylenic protecting groups will be critical to successfully achieve monodeprotection of both symmetrically and orthogonally diprotected polyynes. Results and Discussion Synthesis of Callyberyne A (1). We envisioned that the skeletal framework of callyberyne A (1) could be constructed through two alternative routes involving either Cadiot-Chodkiewicz (sp-sp) or Sonogashira (sp2-sp) cross-coupling reactions as key steps (Scheme 1). Initial efforts led us to consider the Cadiot-Chodkiewicz reaction between the iodotriyne 6 and the monoprotected dienediynes 13 or 17 as the most straightforward disconnection. Thus, 9-iodo-1-triisopropylsilylnona-1,3,8-triyne (6) was easily available from 1-triisopropylsilylnona-1,3,8-triyne (5)25 by treatment with n-BuLi/iodine (89%) (Scheme 2). The monoprotected (3Z,9Z)-1-trimethylsilyldodeca-3,9-diene1,11-diyne (13) and (5Z,11Z)-2-methyltetradeca-5,11-diene-3,13-diyn-2-ol (17) were chosen as suitable building blocks since they could a priori be synthesized by monodeprotection of readily available symmetrically disubstituted precursors (12 and 16, respectively) (Scheme 3). It is well established that bis(trimethylsilyl)acetylenes can be monodesilylated by treatment with MeLi‚LiBr complex in THF followed by hydrolysis.27 Selective unmasking of silyl groups has also been described by employing NaBH(OMe)3.28 As an alternative, partial deprotec(27) (a) Holmes, A B.; Jennings-White, C. L. D.; Schulthess, A. H.; Akinde, B.; Walton, D. R. M. J. Chem. Soc., Chem. Commun. 1979, 840842. (b) Holmes, A. B.; Jones, G. E. Tetrahedron Lett. 1980, 21, 31113112. (c) Eaton, P. E.; Galoppini, E.; Gilardi, R. J. Am. Chem. Soc. 1994, 116, 7588-7596.
Synthesis of Marine Polyacetylenes Callyberynes A-C SCHEME 2
SCHEME 3
tion of bis-tert-propargyl alcohols can be successfully achieved by heating in benzene or toluene solution under basic conditions for short reaction times, a base-catalyzed “retro-Favorsky” elimination of acetone being the driving-force of the reaction.29 Accordingly, the synthesis of the target monoprotected dienediyne 13 started with the preparation of the putative precursor (3Z,9Z)-1,12-bis(trimethylsilyl)dodeca-3,9-diene-1,11-diyne (12), which was obtained in excellent yield by double Sonogashira cross-coupling reaction of dibromide 1025,26 with an excess of trimethylsilylacetylene (11) [PdCl2(Ph3P)2, CuI, piperidine, 95%]. Selective monoprotodesilylation of 12 proved, however, to be discouraging. In fact, the first attempt using 1 equiv of MeLi‚LiBr complex (1.5 M in ether, rt) gave rise to a complex mixture of mono and bis-desilylated products (13 and 14) together with some recovered starting material; the three compounds showed a very similar chromatographic mobilities and product purification was therefore extremely difficult. Disappointingly, the same problem was found when NaBH(OMe)3 or 1 equiv of CsF was used, and therefore, compound 13 could not be prepared efficiently. Due to the difficulties found in the preparation of pure examples of fragment 13, we next focused on the synthesis of (28) (a) Myers, A. G.; Harrington, P. M.; Kuo, E. Y. K. J. Am. Chem. Soc. 1991, 113, 694-695. (b) Wright, J. M.; Jones, G. B. Tetrahedron Lett. 1999, 40, 7605-7609. (29) (a) Ma, L.; Hu, Q.-S.; Pu, L. Tetrahedron: Asymmetry 1996, 7, 3103-3106. (b) Khatyr, A.; Ziessel, R. J. Org. Chem. 2000, 65, 31263134.
(5Z,11Z)-2-methyltetradeca-5,11-diene-3,13-diyn-2-ol (17) (Scheme 3). Palladium-catalyzed double alkynylation of (1Z,7Z)1,8-dibromoocta-1,7-diene (10) with an excess of 2-methyl-3butyn-2-ol (15), under the same above conditions, afforded (5Z,11Z)-2,15-dimethylhexadeca-5,11-diene-3,13-diyne-2,15diol (16) in 84% yield. Rewardingly, partial deprotection of 16 could be achieved by heating its benzene solution at 70 °C for 2 h in the presence of potassium hydroxide, leading to the desired 17 in a moderate 56% yield. Monodeprotected 17 appeared also accompanied by small amounts of fully deprotected (3Z,9Z)-dodeca-3,9-diene-1,11-diyne (14) (14%) and some recovered starting material, but in this case, the polarity of the protecting hydroxyl group allowed an easy chromatographic separation. Attempts to improve the yield by employing longer reaction times, higher temperatures or by changing the solvent (toluene, methanol, i-PrOH) were fruitless, the harshness of the conditions leading to an increase of deprotection or decomposition. With subunits 6 and 17 in hand, Cadiot-Chodkiewicz crosscoupling was carried out under Alami’s improved conditions [CuI, piperidine] to afford (5Z,11Z)-2-methyl-23-triisopropylsilyltricosa-5,11-diene-3,13,15,20,22-pentayn-2-ol (20) in a 60% yield (Scheme 4).30 Unfortunately, the subsequent deprotection step proved again to be troublesome. Attempts to carry out (30) The use of Cadiot-Chodkiewicz classical conditions (5% CuCl, 30% NH2OH, EtNH2, MeOH-H2O) led to a lower yield of cross-coupling product 33 (
